Incidence of cleft lip and palate, and epidemiology of perinatal deaths related to cleft lip and palate in Hunan Province, China, 2016–2020

This study aimed to analyze the epidemiological characteristics of cleft lip and/or palate (CL/P) and CL/P-related perinatal deaths, provide some information for intervention programs to reduce the incidence of CL/P and provide clues for future researchers. Data were obtained from the Birth Defects Surveillance System in Hunan Province, China, 2016–2020. Incidences of CL/P [number of cases per 1000 fetuses (births and deaths at 28 weeks of gestation and beyond)] with 95% confidence intervals (CI) were calculated by residence, gender, maternal age, year, and major types [cleft lip only (CL), cleft palate only (CP), and cleft lip with palate (CLP)]. Crude odds ratios (ORs) were calculated to examine the association of each maternal characteristic with CL/P. Pearson chi-square tests (χ2) were used to examine the association of each maternal characteristic with CL/P-related perinatal deaths. A total of 847,755 fetuses were registered, and 14,459 birth defects were identified, including 685 CL/P (accounted for 4.74% of all birth defects). CL, CP, and CLP accounted for 24.67% (169 cases), 36.79% (252 cases), and 38.54% (264 cases) of all CL/P, respectively. The incidence of CL/P was 0.81‰ (95%CI 0.75–0.87). The incidence of CL was 0.20‰ (95%CI 0.17–0.23) (169 cases), of CP was 0.30‰ (95%CI 0.26–0.33) (252 cases), and of CLP was 0.31‰ (95%CI 0.27–0.35) (264 cases). CL was more common in males than females (0.24‰ vs. 0.15‰, OR = 1.62, 95%CI 1.18–2.22). CP was more common in urban than rural (0.36‰ vs. 0.25‰, OR = 1.43, 95%CI 1.12–1.83), and less common in males than females (0.22‰ vs. 0.38‰, OR = 0.59, 95%CI 0.46–0.75). CLP was more common in males than females (0.35‰ vs. 0.26‰, OR = 1.36, 95%CI 1.06–1.74). Compared to mothers 25–29 years old, mothers < 20 years old were risk factors for CLP (OR = 3.62, 95%CI 2.07–6.33) and CL/P (OR = 1.80, 95%CI 1.13–2.86), and mothers ≥ 35 years old was a risk factor for CLP (OR = 1.43, 95%CI 1.01–2.02). CL/P-related perinatal deaths accounted for 24.96% (171/685) of all CL/P, of which 90.64% (155/171) were terminations of pregnancy. Rural residents, low income, low maternal age, and early prenatal diagnosis are risk factors for perinatal death. In conclusion, we found that CP was more common in urban areas and females, CL and CLP were more common in males, and CL/P was more common in mothers < 20 or ≥ 35 years old. In addition, most CL/P-related perinatal deaths were terminations of pregnancy. CL/P-related perinatal deaths were more common in rural areas, and the proportion of CL/P-related perinatal deaths decreased with the increase in maternal age, parity, and per-capita annual income. Several mechanisms have been proposed to explain these phenomena. Our study is the first systematic research on CL/P and CL/P-related perinatal deaths based on birth defects surveillance. It is significant for intervention programs to prevent CL/P and CL/P-related perinatal deaths. As well, more epidemiological characteristics of CL/P (such as the location of CL/P) and approaches to reduce CL/P-related perinatal deaths need to be studied in the future.


Scientific Reports
| (2023) 13:10304 | https://doi.org/10.1038/s41598-023-37436-y www.nature.com/scientificreports/ Cleft lip and/or palate (CL/P) are classified as cleft lip only (CL), cleft palate only (CP), and cleft lip with palate (CLP) 1 . It significantly impacts life quality, healthcare use, and costs of patients and their families 2,3 and increases the risk of perinatal deaths. CL/P are common congenital malformations affecting the head and neck and one of the most common birth defects 4 . The global incidence of CL/P is reported to be 1.08‰ 5 . Previous studies have shown Asia's highest incidence of CL/P 4,6-8 . China is one of the regions with the highest incidence of CL/P. E.g., a meta-analysis in China  showed that the overall incidence of orofacial clefts [referred to all types of clefts (CP, CL, or CLP; syndromic or nonsyndromic forms)] was 1.4 per 1000 live births 9 .
Through prenatal screening and diagnosis, doctors can diagnose CL/P early and reduce the incidence 10 . Therefore, studies on the epidemiological characteristics of CL/P are essential for providing evidence for future intervention. However, the epidemiology of CL/P and CL/P-related perinatal deaths have rarely been reported recently. More studies need to be included. Therefore, we investigated the epidemiology of CL/P and CL/P-related perinatal deaths in Hunan Province, China, using data from the Birth Defects Surveillance System in Hunan Province, 2016-2020. This study aimed to provide some information for intervention programs to reduce the incidence of CL/P and to provide clues for future researchers.

Methods
Data sources. This study used data from the Birth Defects Surveillance System in Hunan Province, China, 2016-2020, which is run by the Hunan Provincial Health Commission and involves 52 representative registered hospitals in Hunan Province. Surveillance data of fetuses (births and deaths at 28 weeks of gestation and beyond) and all birth defects (between 28 weeks of gestation and 7 days after delivery) included demographic characteristics such as residence, gender, maternal age, and other key information.
According to the WHO International Classification of Diseases (Ninth Revision, ICD-9), the ICD code of CL is Q36, CP is Q35, and CLP is Q37.
Informed consents. We confirmed that informed consent was obtained from all subjects and/or their legal guardian(s). Doctors obtain consent from pregnant women before collecting surveillance data, which is witnessed by their families and the heads of the obstetrics or neonatal departments. Doctors obtain consent from their parents or guardians for live births, which are witnessed by their families and the heads of the obstetrics or neonatal departments. Since the Health Commission of Hunan Province collects those data and the government has emphasized the privacy policy in the "Maternal and Child Health Monitoring Manual in Hunan Province", there is no additional written informed consent.

Ethics guideline statement. The Medical Ethics Committee of Hunan Provincial Maternal and Child
Health Care Hospital approved the study (NO: 2022-S94). It is a retrospective study of medical records; all data were fully anonymized before we accessed them. Moreover, we de-identified the patient records before analysis. We confirmed that all experiments were performed following relevant guidelines and regulations.

Data quality control.
To carry out surveillance, the Hunan Provincial Health Commission formulated the "Maternal and Child Health Monitoring Manual in Hunan Province". Data were collected and reported by experienced doctors. To reduce the integrity rate and information error rate, we asked the technical guidance departments to carry out comprehensive quality control each year. Statistical analysis. The incidence of CL/P is defined as the number of cases per 1000 fetuses (births and deaths at 28 weeks of gestation and beyond) (‰). We computed the incidences of CL/P (CL, CP, and CLP) and 95% confidence intervals (CI) by Poisson's regression. Crude odds ratios (ORs) were calculated to examine the association of each maternal characteristic with CL/P. Chi-square trend tests (χ 2 trend ) were used to determine trends in incidences of CL/P by year. Pearson Chi-Square tests (χ 2 ) were used to examine the association of each maternal characteristic with CL/P-related perinatal deaths.

CL/P in
CL was more common in males than females (0.24‰ vs. 0.15‰, OR = 1.62, 95%CI 1.18-2.22). CP was more common in urban than rural (0.36‰ vs. 0.25‰, OR = 1.43, 95%CI 1.12-1.83) and less common in males than females (0.22‰ vs. 0.38‰, OR = 0.59, 95%CI 0.46-0.75). CLP was more common in males than females (0.35‰ vs. 0.26‰, OR = 1.36, 95%CI 1.06-1.74). Compared to mothers 25-29 years old, mothers < 20 years old were a risk factor for CLP (OR = 3.62, 95%CI 2.07-6.33) and CL/P (OR = 1.  Table 3 shows the detailed incidences of CL/P by year. CL/P-related perinatal deaths. CL/P-related perinatal deaths accounted for 24.96% (171/685) of all CL/P, and 90.64% (155/171) of CL/P-related perinatal deaths were terminations of pregnancy. Perinatal deaths due to CL, CP, and CLP accounted for 8.88%, 3.97%, and 55.30% of all cases, respectively. And terminations of pregnancy due to CL, CP, and CLP accounted for 80.00%, 50.00%, and 94.52% of all deaths, respectively. The proportion of CLP-related perinatal deaths was relatively high. (χ 2 = 212.38, P = 0.00). Table 4 shows the details of CL/P-related perinatal deaths. Table 5 showed the following epidemiological characteristics of CL/P-related perinatal deaths: (1) CL/P-related perinatal deaths were more common in rural than urban areas. (2) The proportion of CL/P-related perinatal deaths decreased with the increase in maternal age,  (3) The proportion of CL/P-related perinatal deaths was higher in the B-Ultrasound diagnosis group. And the earlier the diagnosis, the higher the proportion of CL/P-related perinatal deaths. Table 5 shows the detailed epidemiology of CL/P-related perinatal deaths.

Discussion
Overall, we found a relatively high incidence of CL/P, and residence, gender, and maternal age impacted the incidence of CL/P. In addition, we found that CL/P-related perinatal deaths were associated with some epidemiological characteristics. The incidence of CL/P (0.81‰) in our study is lower than the global incidence (1.08‰) or the reported incidence in China (1.4‰) 5,9 . Another comprehensive study by Cooper et al. also reported higher incidences of CL/P than ours: the incidences of CL/P in Chinese, Japanese, and other Asians were 1.30‰, 1.34‰ and 1.47‰, and the total incidence of CL/P in Asians was 1.33‰ (2006) 11  There are significant differences between them. And it seems the incidences of CL/P were higher in high-income countries. Several studies have also reported incidences of CL, CP, and CLP. E.g., the global incidences of CL, CP, and CLP were 0.3‰, 0.33‰, and 0.45‰, respectively 5 ; The incidences of CL, CP, and CLP in South Korea were 0.28‰, 0.56‰ and 0.27‰ respectively 12 ; The incidences of CL, CP, and CLP in Guangdong Province, China, were 0.23‰, 0.22‰ and 0.30‰, respectively 17 ; The incidences of CL, CP, and CLP in Fangshan District, Beijing, China, were 0.62‰, 0.34‰ and 0.94‰, respectively 18 . There are also significant differences between them.
We infer that several factors may be related to these differences. First, it may reflect the frequency of defective genes for CP/L in different regions. E.g., Mitchell et al. found that the incidence of CL/P was higher in Asians than Caucasians than Africans 6 . Second, differences in access to diagnostic services may contribute to these results. Better access to diagnostic services for pregnant women in high-income countries resulted in more defects being detected 19 . The reason for the lower incidence of CL/P in this study may also be mainly related to prenatal screening and diagnosis (such as the use of B-ultrasound), and many fetuses with CL/P were diagnosed and terminated before 28 weeks of gestation. Third, some other factors may also be related to these differences. E.g., many studies mentioned above include relatively few cases or limited data.
We also found that CL/P was associated with residence, gender, and maternal age. E.g., CP was more common in urban than rural areas. It is consistent with some studies in low-and middle-income countries, such as Brazil and Jordan 20,21 , and inconsistent with some studies in high-income countries, such as the US and South Korea 22,23 . It may be mainly related to lower access to healthcare and diagnostic technologies for birth defects in rural areas 24 . In addition, some adverse conditions in urban areas may also contribute to this phenomenon, such as air pollution [25][26][27][28] . CL and CLP were more common in males, while CP was more common in females. It is consistent with previous studies 14, [29][30][31][32] . The higher incidences of CL and CLP in males might be caused by the higher sensitivity of male fetuses to environmental stress, leading to the appearance of congenital birth defects 14,33 . CL/P was more common in mothers < 20 or ≥ 35 years old. It is consistent with previous studies [34][35][36][37][38] . It may be related to low-quality oocytes and semen for parents aged ≥ 35 years old 34,[39][40][41] . And mothers < 20 years old may lack physical maturity and have a deficiency in vitamins (such as folic acid), which has been associated with birth defects 42 .  www.nature.com/scientificreports/ In addition, we found that CL/P-related perinatal deaths were associated with residence, maternal age, income, parity, methods, and time of diagnosis. It has been rarely reported recently. First, CL/P-related perinatal deaths were more common in rural areas, and the proportion of CL/P-related perinatal deaths decreased with the increase in maternal age, parity, and per-capita annual income. And more than 90% of CL/P-related perinatal deaths were terminations of pregnancy. It suggests that CL/P-related perinatal deaths may be mainly related to economic conditions [43][44][45][46] . CL/P significantly impacts babies' life quality, healthcare use, and costs of patients and their families 7 . Therefore, better economic conditions benefit children's treatment and may make birth more likely. Second, CL/P-related perinatal deaths were associated with the methods and time of diagnosis. It is mainly concerned with the health of mothers. On the one hand, most CL/P-related perinatal deaths are therapeutic terminations of pregnancy 4,47 . On the other hand, the earlier CL/P is diagnosed and terminated, the less adverse impact termination has on mothers and their families. Therefore, most mothers terminate as soon as possible after diagnosing CL/P. Currently, B-Ultrasound is the most common and effective prenatal screening and diagnostic method, and many CL/P can be detected early in pregnancy by B-Ultrasound. Therefore, the proportion of CL/P-related perinatal deaths was higher in the B-Ultrasound diagnosis group.
Some things could be improved in our study. E.g., we did not analyze some epidemiological features due to data limitations, including the father's information and the location of CL/P (left, center, or right). To address these limitations, first, the Monitoring Manual for Birth Defects Surveillance needs improvement; second, more studies should focus on the epidemiological characteristics of CL/P.

Conclusion
In conclusion, we found that CP was more common in urban areas and females, CL and CLP were more common in males, and CL/P was more common in mothers < 20 or ≥ 35 years old. In addition, most CL/P-related perinatal deaths were terminations of pregnancy. CL/P-related perinatal deaths were more common in rural areas, and the proportion of CL/P-related perinatal deaths decreased with the increase in maternal age, parity, and per-capita annual income. Several mechanisms have been proposed to explain these phenomena. Our study is the first systematic research on CL/P and CL/P-related perinatal deaths based on birth defects surveillance. It is significant for intervention programs to prevent CL/P and CL/P-related perinatal deaths. As well, more epidemiological characteristics of CL/P (such as the location of CL/P) and approaches to reduce CL/P-related perinatal deaths need to be studied in the future.

Data availability
All data generated or analysed during this study are included in this published article.